Abstract: Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries for those over 55. AMD is a complex and multi-factorial disease described as two distinct types, dry and wet, leading to central vision loss. Dry AMD is characterized by the subretinal accumulation of deposits (drusen) and is associated with the progressive atrophy of the retinal pigment epithelium (RPE), choriocapillaris (vasculature supplying the photoreceptors) and retinal neurons. Dry AMD can progress to the proliferative form, wet AMD, where pathological and highly permeable vessels grow into the subretinal space. There is no treatment for dry AMD and the current anti-angiogenic therapies for wet AMD, though effective at reducing vessel growth and permeability, do not address the underlying pathogenesis. Thus, the need for new therapeutic approaches is clear. Abnormalities in the RPE and the Bruch's membrane (BrM), on which the RPE sit, are central to the development of AMD. Therefore, we are proposing a novel transplantation strategy to replace the degenerative RPE/BrM with the goal of preserving the choriocapillaris integrity and photoreceptor function. Previous attempts to transplant the RPE have failed largely because BrM alterations were not addressed. The aim of this proposal is to develop a co-culture system of RPE and endothelial cells on a biodegradable, biocompatible poly([unreadable]-caprolactone) (PCL) polymer to bioengineer a RPE/Bruch's membrane complex. The differentiation of the RPE and the formation of the BrM like matrix on the PCL scaffold will be evaluated by immunohistochemistry, gene expression analysis and electron microscopy techniques. Finally, the therapeutic potential of the RPE-PCL transplantation for patients with AMD will be determined in animal models of RPE damage. Results of these studies may permit the development of strategies aimed at replacing the diseased subretinal tissue with a bioengineered RPE/BrM prosthesis that could represent a therapeutic solution for all forms of AMD. Public Health Relevance: Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population of industrialized countries. We propose to develop a novel strategy for vision restoration in advanced AMD using a bioengineered Bruch's membrane transplant. By reconstructing damaged retinal tissue, this approach may represent an effective treatment for AMD.